The present invention relates to a novel dermal filler composition and a method of preparing the same, in which the composition can rapidly give any shapes by being injected into the body via a syringe.
Soft tissues of the human body maintain their structures by an extracellular matrix including protein, such as collagen and elastin, and glycosaminoglycan. When the defects of the soft tissues are caused by congenital factors, external stimulations, pathological factors, and the like, their shapes have been restored and reformed by inserting body tissues or synthetic polymer chemical materials into a relevant part to expand the soft tissues. Meanwhile, the material to be used for an improvement in wrinkles, a reformation in outline, and the like by injecting a component that is similar to skin tissues into a specific part via a syringe to expand the soft tissues, is generally called a dermal filler or a filler. The dermal fillers may be classified into the following two types depending on a functional mechanism for effect. One is the dermal filler, in which an injected material has the effect of expanding through a direct tissue-volume augmentation, and the other is the dermal filler, in which the injected material stimulates the materials to newly produce autologous tissues, such as collagen, around an injection part to exhibit the tissue-volume augmentation effect, in addition to the direct tissue-volume augmentation effect by the injected material.
In addition, dermal fillers may also be classified into the following three types depending on an effectual period.
Dermal fillers can be classified into the following types: first, a dermal filler is rapidly decomposed and absorbed within one year; second, a dermal filler has the period of decomposition longer than that of the dermal filler rapidly decomposed and absorbed within one year, but is eventually decomposed and absorbed; and third, a dermal filler is not decomposed, but is permanently maintained in vivo.
Collagen, hyaluronic acid, and the like, which are most frequently used now as a main component of the dermal filler, are corresponded to the dermal filler which is rapidly decomposed and absorbed within one year while exhibiting the effect of expanding by direct increasing a tissue-volume. Polyacrylamide components are corresponded to the dermal filler which is not decomposed but is permanently maintained in vivo while exhibiting the effect of expanding by directly increasing the tissue-volume. Polymethylmethacrylate (PMMA) corresponds to the dermal filler which is not decomposed and thus is permanently maintained in vivo while stimulating materials to newly produce autologous tissues, such as collagen, around an injection part to exhibit the tissue-volume augmentation effect, in addition to a direct tissue-volume augmentation effect by an injected material. And also, cross-linked dextran corresponds to the dermal filler which has the period of the decomposition longer than that of the dermal filler rapidly decomposed and absorbed within one year, but is eventually decomposed and absorbed, while stimulating the materials to newly produce autologous tissues, such as collagen, around the injection part to exhibit the tissue-volume augmentation effect in addition to the direct tissue-volume augmentation effect by the injected material.
The preferable dermal filler is required to have the following several conditions. First, it should have excellent biocompatibility and be safe; second, it should be practically a small burden because of a low cost; and third, a tissue-volume augmentation effect of grafted area should be continued over a long period of time, i.e., at least 2 years.
As the dermal filler currently in use, there are many products having collagen or hyaluronic acid, respectively, as a main component. First, as the dermal fillers having collagen as a main component, EVOLENCE 30 (Trademark of dermal filler available from ColBar LifeScience) having porcine collagen as a main component, Zyderm or Zyplast (Trademarks of dermal filler available from Inamed) having bovine collagen as a main component, CosmoDerm or CosmoPlast (Trademarks of dermal filler available from Inamed) having human collagen as a main component, and the like are known. As the dermal fillers having hyaluronic acid as a main component, Rofilan (Trademark of dermal filler available from Rofil/Philoderm), Perlane and Restrylane (Trademarks of dermal filler available from Medicis/Q-Med AB-), Teosyal (Trademark of dermal filler available from Teoxane SA), Surgiderm (Trademark of dermal filler available from Corneal Laboratoire), and the like are known. However, the dermal fillers having only collagen or hyaluronic acid as a main component are expensive, but their effect continuance times are very short. Therefore, their actual applications are limited in a clinical field.
Moreover, there are MATRIDEX and CRM Dx (Trademarks of dermal filler available from BioPolymer GmbH & Co. KG) having hyaluronic acid and cross-linked dextran (DEAE Sephadex) as a main component for products having a little longer effect continuance time. In the case of the dermal filler consisting of hyaluronic acid and cross-linked dextran particles as a main component, a tissue-volume augmentation effect is immediately caused after injection, the hyaluronic acid is decomposed and absorbed over 6 to 12 months, and then the empty space produced is filled with autologous collagen newly produced by a stimulation of the cross-linked dextran. The hyaluronic acid is a cellular matrix component between epidermis and dermis; and serves to conjugate cells each other and serves as a lubricant among cells. The hyaluronic acid used in the dermal filler for injection is artificially synthesized. For a period of effect, the hyaluronic acid is eventually decomposed and then disappeared within one year; and the cross-linked dextran is continued for 1 to 2 years that is longer than less than one year and then eventually all of them is decomposed and disappeared. However, the effect is continued a little longer by newly forming an autologous tissue, such as collagen. However, there is a disadvantage that the dermal filler has become so expensive because the hyaluronic acid occupies most of the product.
There is Artefill (Trademark of dermal filler available from Artes Medical Co.) having polymethylmethacrylate (PMMA) and collagen as a main component for a product having an effect for a longer period of time as compared with the above dermal fillers including the cross-linked dextran. First, bovine collagen is purified and then made in a liquid state; and polymethylmethacrylate (PMMA) is mixed to prepare dermal filler; and then the dermal filler is injected under dermis to maintain a tissue-volume augmentation effect. In the case of the above dermal filler, there is an advantage that the tissue-volume augmentation effect is maintained by producing an augmentation effect immediately after an injection of polymethylmethacrylate (PMMA) and then filling an empty space produced through the decomposition and absorption of the collagen with autologous collagen newly produced by a stimulation of polymethylmethacrylate (PMMA). However, it is the biggest barrier for an actual clinical application because the used collagen is derived from an animal, i.e., bovine extracts so that a pre-treatment, such as an allergic skin test, is surely required before use. In addition, there are disadvantages that collagen component is very expensive so that financial burdens of patient is greatly increased upon a surgical operation and the collagen component that occupies most of the product volume is excessively rapidly decomposed and absorbed in vivo upon an injection (all of collagen is absorbed only within 3 to 6 weeks) thereby not assuring the volume maintenance through new collagen formation. In addition, since the polymethylmethacrylate (PMMA) component is not decomposed and thus permanently remains in vivo, there is an indefinite fear for the possibility of side effect in the distant future. For this reasons, its use may be limited.
In addition, US Patent Application Publication No. 2003/0233150 by Bourne at al. discloses a composition including polymethylmethacrylate (PMMA) as a basic polymer and dextran and the like as a carrier for restoring or expanding body tissues. However, as disclosed above, the composition as disclosed in US Patent Application Publication No. 2003/0233150 may have a possibility of side effect because the polymethylmethacrylate (PMMA) component is not decomposed and permanently remains in vivo. In addition, when cross-linked dextran is injected into tissue, a part thereof functions as augmenting directly a tissue-volume and at the same time, is not eaten by macrophage and causes a foreign reaction in the body for a predetermined period of time so that it can induce an autologous collagen formation for the expansion function. However, the dextran used in the above US Patent Application Publication No. 2003/0233150 by Bourne at al. has an disadvantage that it is decomposed within several days after injecting in vivo so that the dextran is only a simple carrier because the dextran cannot have an tissue-volume augmentation effect.
Recently, a dermal filler composition having polymethylmethacrylate (PMMA) and cross-linked dextran as a main component (Korean Patent No. 10-0759091) has been developed so that some of problems of the dermal fillers in the related art as disclosed above have been improved.
The composition eliminates the necessity of a pretreatment, such as an allergy test, which might otherwise be required prior to injection, is inexpensive, and is not easily decomposed or absorbed in vivo, thereby maintaining the effect thereof over a long period of time. Therefore, the composition is suitable for use in a procedure such as injection penile augmentation which requires the injection of a large amount of dermal filler, i.e., more than 20 cc. However, the composition has a disadvantage that the composition is a little bit hard to the touch when injected under the skin so that the composition is suitable for injection penile augmentation, but not suitable for other wide parts of the human body including the face, which requires more soft touch.
In addition, it is more difficult to put the dermal filler to practical use because of the complication of preparing process due to a mixing process of two major polymers and a difficulty for obtaining permission to use in a human body.
In addition, since polymethylmethacrylate (PMMA) component is not decomposed and thus permanently remains in vivo, there is an indefinite fear for the possibility of side effect in the distant future.
Meanwhile, there is no dermal filler that uses only cross-linked dextran as a main component among dermal fillers. The reason is that the cross-linked dextran, which is incidentally used in all of the dermal fillers in the related art, has a molecular weight of less than 30,000 (Product Name: DEAE Sephadex 25); a bead size in a dried state is 40 to 120 μm; a diameter of intermediate value of the bead size is 127 μm when it is hydrated in an aqueous solution of 0.15 M sodium chloride; and a ratio of diameters of hydrated state/dried state is 1.83 (6.1 in a ratio of volumes thereof) so that a tissue-volume augmentation effect is very small; also it is difficult to inject without a carrier and thus a carrier having a volume augmentation effect, such as collagen or hyaluronic acid is required; and touch of injection part is very hard due to a hard capsule produced by a tissue reaction (see FIG. 2). Therefore, there are disadvantages that the cross-linked dextran in the related art is not suitable for being a single main component in filler due to a difficult of injection and a hard touch around the injection part when the cross-linked dextran is used alone and it is surely required to add a material, such as collagen or hyaluronic acid, as a carrier and also a main component.